A. Introduction. Myeloproliferative neoplasms and myelodysplastic disorders are often confused. They are, in fact, different entities.
a. Myeloproliferative neoplasms (MPNs) are a group of clonal myeloid neoplasms in which a hematopoietic progenitor proliferates, leading to an increase in peripheral blood white blood cells (WBCs), red blood cells (RBCs), platelets, or a combination of these.
b. Myelodysplastic syndrome (MDS) is also a group of clonal myeloid neoplasms that result in ineffective hematopoiesis. This may lead to a hypercellular or hypocellular bone marrow with a decrease in circulating WBCs, RBCs, platelets, or a combination of these. The hallmark of MDS is dysplasia: the unusual appearance of myeloid precursors in the bone marrow.
B. Myeloproliferative Neoplasms
i. Types of disorders. There are four primary myeloproliferative neoplasms. They all involve clonal proliferation of a hematopoietic progenitor cell, leading to both qualitative and quantitative changes in all cell lines. While the name of the disorder typifies the predominant cell line that is affected, more than one cell line is affected in most of these disorders.
1. Chronic myeloid leukemia (CML) is characterized by a prominent proliferation of myeloid progenitor cells, leading to an expansion of the granulocytic series of cells resulting in a “left shift”—an increase in immature granulocytes of all stages of maturation in the peripheral blood.
2. Polycythemia vera (PV) is characterized by prominent proliferation of myeloid progenitor cells, leading to elevated RBC indices (RBC count, hemoglobin, and hematocrit).
3. Essential thrombocytosis (ET) is characterized by prominent proliferation of megakaryocytes, leading to an elevated platelet count.
4. Primary myelofibrosis (PMF) is characterized by a proliferation of myeloid progenitor cells that leads to a prominent nonclonal proliferation of fibroblasts. The resulting deposition of reticulin and collagen leads to fibrosis (scarring) of the bone marrow. Compared with the other MPNs, patients with PMF often have low blood counts due to the fibrosis.
1. Primary abnormality (Table 70.1)
a. In CML, the predominant feature is usually a leukocytosis with a left shift. Mild anemia, normal to elevated platelet count, and peripheral blood basophilia and eosinophilia are often seen.
b. In PV, the predominant features are elevated RBC indices (RBC count, hemoglobin, and hematocrit). Patients may also have a mild leukocytosis and thrombocytosis.
c. In ET, the predominant feature is an elevated platelet count. Patients often also have a mild leukocytosis and polycythemia.
d. In PMF, the predominant feature is evidence of extramedullary hematopoiesis in the form of hepatomegaly and splenomegaly. Patients often have an anemia, but their WBC and platelet counts can be variable. Leukoerythroblastic changes (teardrop cells, nucleated RBCs, and early myeloid progenitors [blasts]) are often seen in the peripheral blood.
Table 70.1 2016 World Health Organization Diagnostic Criteria for Myeloproliferative Neoplasms1
Polycythemia Vera (PV)2
Essential Thrombocytosis (ET)5
1. Elevated red blood cell indices3
1. Platelets ≥450 X 109 cells/L
1. Presence of megakaryocytic proliferation and atypia, accompanied by reticulin and/or collagen fibrosis
2. BM biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation
2. BM biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of megakaryocytes with hyperlobulated nuclei.
2. Not meeting criteria for PV, ET, CML, or MDS
3. Presence of JAK2 V617F or JAK2 exon 12 mutation4
3. Not meeting criteria for PV, PMF, CML, or MDS
3. Presence of JAK2, CALR, or MPL mutation or, in the absence of these mutations, presence of another clonal marker or absence of reactive myelofibrosis6
4. Presence of JAK2, CALR, or MPL mutation6
1. Subnormal serum erythropoietin level
1. The presence of a clonal marker or absence of evidence for reactive thrombocytosis
1. Anemia not attributed to a comorbid condition
2. Leukocytosis >11X109/L
3. Palpable splenomegaly
4. LDH >upper limit of normal
1 Adapted from Arber, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391–2405.
2 The diagnosis of PV requires meeting either all three major criteria or the first two major criteria and the minor criterion.
3 The following constitute elevated red blood cell indices: (A) a hemoglobin of >16.5 g/dL in men or 16 g/dL in women, (B) an elevated hemoglobin or hematocrit >49% in men and >48% in women, or (C) a red blood cell mass >25% above the mean normal predicted value.
4 The JAK2 tyrosine kinase sequence is evaluated for the presence of the V→F mutation at codon 617. Additionally, mutations in exon 12 of JAK2 can fulfill this criterion.
5 The diagnosis of ET requires meeting all four major criteria or the first three major criteria and the minor criterion.
6 The JAK2 tyrosine kinase sequence is evaluated for the presence of the V→F mutation at codon 617. Additionally, mutations in exon 12 of JAK2, c-Mpl mutations, or mutations in calreticulin (CALR) can fulfill this criterion.
7 The diagnosis of primary myelofibrosis requires meeting all three major criteria, and at least one minor criterion.
BM = bone marrow; CML, chronic myelogenous leukemia; LDH = lactate dehydrogenase; MDS = myelodysplastic syndrome.
2. Multiple abnormalities. The presence of multiple blood count abnormalities in MPN is common, making diagnosis based on CBC abnormalities alone difficult. The following clinical features can help suggest a specific myeloproliferative neoplasm:
a. Massive splenomegaly (see Chapter 31) implies CML, PMF, or late stage PV/ET.
b. A decreased leukocyte alkaline phosphatase (LAP) score is seen in CML, although this test is rarely used today.
c. Nucleated RBCs, early WBCs, and abnormal RBC morphology (i.e., teardrop cells) are characteristic of a leukoerythroblastic smear and are seen in PMF or in the late stages of ET or PV.
i. Approach to the patient
1. Patient history
a. Common complaints include fevers, sweats, fatigue, and abdominal fullness (from splenomegaly).
b. Significant leukocytosis (e.g., a WBC count >300,000 cells/μL) may cause leukostasis. Symptoms of leukostasis include headaches, blurred vision, chest pain, respiratory distress, and priapism and require emergent medical treatment (leukapheresis).
2. Physical examination. Significant splenomegaly is a common finding.
3. Laboratory studies
a. WBC count. The WBC count can be significantly elevated. The WBC differential demonstrates a left shift with nearly all granulocytic precursors represented. Eosinophilia and basophilia are often present.
b. Peripheral blood smear. Typically, myeloid forms in varying degrees of maturation (left shift) are seen.
c. Vitamin B12 and uric acid levels may be increased as a result of increased transcobalamin secretion and high cell turnover, respectively.
4. Bone marrow biopsy. A hypercellular marrow for age with left-shifted WBCs is usually seen. Eosinophilia and basophilia can also be noted. When the disease progresses to the accelerated or blast phase, the peripheral blood and/or bone marrow has an elevated blast percentage (10%–19% for accelerated phase and ≥20% for blast phase). Profound fibrosis is also suggestive of progressive CML.
5. Cytogenetic studies. The sine qua non of CML is the identification of the translocation of the Abl tyrosine kinase on chromosome 9 to a region within the breakpoint cluster region (Bcr) of chromosome 22, resulting in the Philadelphia chromosome [t(9;22)] and the aberrant expression of the Bcr-Abl tyrosine kinase. The fusion can be identified by classic cytogenetics, fluorescence in situ hybridization (FISH) testing, or reverse transcriptase polymerase chain reaction (RT-PCR) analysis. It is essential to assess the karyotype as well as quantify the Bcr-Abl RT-PCR product at the time of diagnosis.
1. Leukapheresis is indicated if the patient has symptoms of leukostasis, which is a medical emergency.
a. Hydroxyurea is usually used to acutely lower the WBC count while awaiting a diagnostic workup.
b. Interferon-α (IFN-α) is a historical therapy rarely used today other than in pregnant women requiring treatment before delivery.
c. Selective tyrosine kinase inhibitors (TKIs), including imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) have become the mainstays in the treatment of patients with newly diagnosed CML. They work by selectively binding and inhibiting the Bcr-Abl tyrosine kinase. They have been shown to induce complete hematologic and cytogenetic remissions in most CML patients. Survival has dramatically improved with the current 10-year leukemia-specific survival rate being about 92%.
3. Allogeneic bone marrow transplantation offers the only possibility for cure. However, given the effectiveness of oral TKIs and the morbidity and mortality of transplantation, this has generally been reserved for patients with relapsed or refractory disease.
iii. Prognosis. With the introduction of the TKIs, 10-year survival is excellent. However, approximately 15–20% of patients will be resistant or intolerant to the first TKI that they use. Second- and third-generation TKIs (dasatinib, nilotinib, bosutinib, and ponatinib) provide excellent treatment alternatives. Allogeneic transplantation also remains an option.
i. Approach to the patient
1. Patient history
a. Symptoms of hyperviscosity are occasionally seen (e.g., headaches, dizziness, blurred vision).
b. Venous or arterial thrombosis may also be the presenting finding.
c. Basophil/mast cell release of histamine or alterations in prostaglandin production may account for the high incidence of both pruritus and peptic ulcers.
d. Facial plethora (ruddy cyanosis) is a common finding.
Think of PV when a patient is admitted with a bleeding peptic ulcer but continues to have a normal or elevated hematocrit.
2. Physical examination. Splenomegaly can be found on examination but is not as marked as in CML and PMF. Facial plethora, gouty arthritis, and tophi can be indications of the hyperproliferative marrow.
3. Laboratory studies (see Table 70.1). The original diagnostic criteria for PV were established in the late 1960s by the Polycythemia Vera Study Group (PVSG). Newer guidelines (2016 World Health Organization [WHO]) incorporate the morphologic and molecular biology of the disease.
a. Hematocrit. Elevated RBC indices are nearly universal in PV, but secondary causes of polycythemia must be ruled out first.
b. Mean corpuscular volume (MCV). In nearly all patients, there is an associated iron deficiency, and some patients will have a microcytosis (low MCV). Gastrointestinal bleeding from engorged vessels or peptic ulcer disease and increased demand from the overproduction of RBCs are potential etiologies of iron deficiency.
c. Erythropoietin level. The erythropoietin level is usually low (<2 mU/mL).
d. RBC mass assay may help establish true elevated red cell volume versus a depressed plasma volume leading to an elevated hematocrit in secondary polycythemia.
e. Although an elevated LAP score or an elevated serum B12 level can be seen in PV, neither is sensitive or specific, and these tests are not used in newer diagnostic guidelines (see Table 70.1).
4. Bone marrow biopsy. A bone marrow biopsy will reveal an increased number of myeloid, erythroid, and megakaryocytic progenitors (panmyelosis). Iron stores are decreased in nearly all patients. The procedure may help also help evaluate for other causes of abnormal blood counts as well as evaluating for progression of polycythemia to the spent or fibrotic phases.
5. JAK2 mutation assessment. A mutation in the Janus kinase-2 (JAK2) gene (either the V617F or exon 12 mutation) has been identified in nearly all patients with PV, and may play a role in the propagation of the disease.
ii. Treatment. The major goal of the treatment of PV is to reduce the thrombotic risk by lowering the hematocrit.
1. Phlebotomy may be performed weekly until the hematocrit has been lowered to <45%; thereafter, maintenance phlebotomy may be performed as needed.
2. Pharmacologic therapy
a. Hydroxyurea is added to phlebotomy in patients with elevated risk factors for thrombotic complications from their PV including: age >60 years, prior thrombosis, or platelet count >1,500,000/μL.
b. Aspirin in low doses (e.g., 81 mg/day) should be given to all patients with PV assuming there is no medical contraindication.
c. Alkylating agents and radiophosphorus can be leukemogenic and are increasingly avoided.
iii. Prognosis. The median survival with treatment is 10–15 years. PV can progress to the spent phase with “normalization” of blood counts, followed by a fibrotic phase (i.e., post-PV myelofibrosis), and rarely acute myelogenous leukemia (AML).
i. Approach to the patient
1. Patient history
a. Abnormalities in platelet function can lead to both thromboses and bleeding. Erythromelalgia (i.e., intense, burning pain in dependent extremities often accompanied by skin warmth and mottling) results from microvascular occlusion. Although it can occur in all myeloproliferative disorders, erythromelalgia is especially common in patients with ET. Other possible symptoms include headache, atypical chest pain, and livedo reticularis. It is important to document previous thrombotic events as well as symptoms related to a stroke or transient ischemic attack.
b. In many patients, ET is asymptomatic.
2. Physical examination. Approximately one-fourth to one-half of patients have splenomegaly, but this is not as common as in CML or PMF.
a. Platelet count. The platelet count is invariably greater than 450,000 cells/μL and can exceed 1,000,000 cells/μL.
b. Peripheral blood smear. The platelet morphology is frequently abnormal, with many small and many large platelets resulting in a high platelet distribution width.
c. Bleeding times and aggregation studies may show abnormalities in platelet function. As platelet levels rise to >1,000,000 cells/μL, the risk for acquired von Willebrand’s disease increases, resulting in a paradoxical increased risk for bleeding.
4. Bone marrow biopsy. This often reveals an increased number of large, hyperlobulated megakaryocytes that tend to form clusters. This finding contrasts with that of reactive thrombocytosis in which megakaryocytes have a normal morphology and random distribution.
5. JAK2 mutation assessment. A mutation in the Janus kinase-2 (JAK2) gene (V617F) has been identified in approximately 50% of patients with ET and may play a role in the propagation of the disease. Moreover, mutations in calreticulin (CALR) or the thrombopoietin receptor (MPL) gene may be seen. However, the presence or absence of a mutation does not rule in or rule out the diagnosis.
ii. Treatment. The goal of therapy in ET is to minimize the risk for thrombotic complications. Therefore, several strategies have been suggested to stratify an individual’s risk factors for thrombosis and to determine when to initiate treatment.
1. Low-risk patients (age <60 years, no history of thrombotic events, and platelet counts ≤1,500,000 cell/μL) often require no therapy other than a low dose of aspirin.
2. High-risk patients (age ≥60 years, previous history of thrombosis, or platelet counts ≥1,500,000 cell/μL) often require cytoreductive therapy. Treatment includes:
a. Aspirin. Small daily doses (e.g., 81 mg/day) are indicated for both low- and high-risk patients to minimize thrombotic complications. Aspirin may also help control vasomotor symptoms.
b. Hydroxyurea is often used as a first-line therapy for high-risk patients and can effectively reduce the risk for thrombosis.
c. Anagrelide is an effective oral agent to lower the platelet count. However, in a study comparing hydroxyurea with anagrelide, the composite endpoint of arterial or venous thrombosis, bleeding, or death from any causes was higher in patients treated with anagrelide. Therefore, it is usually a second-line therapy.
3. IFN-α has been used to control thrombocytosis, but given numerous side effects, it is rarely used.
4. Alkylating agents and radiophosphorus are increasingly avoided.
iii. Prognosis. ET is an indolent disease. The average survival time is usually at least 10–15 years.
i. Approach to the patient
1. Patient history. Symptoms related to anemia (fatigue, dyspnea), thrombocytopenia (easy bruisability), neutropenia (infections), night sweats, bone pain, and marked splenomegaly (abdominal distention, early satiety, and weight loss).
PMF was previously called chronic idiopathic myelofibrosis or agnogenic myeloid metaplasia.
2. Physical examination. Splenomegaly is usually very pronounced, and hepatomegaly may also be present.
3. Laboratory studies
a. Hematocrit. Anemia is seen in 50% of patients. There is more variability in the platelet and WBC counts, although most have suppressed WBCs and platelet counts.
b. Peripheral blood smear. The combination of teardrop cells, a leukoerythroblastic smear (nucleated RBCs and left-shifted WBCs), and large, abnormal platelets is often seen in PMF.
4. Bone marrow biopsy is required to make the diagnosis and reveals an increase in the deposition of reticulin fibers in the early stages of disease and more severe fibrosis (collagen fibrosis) later in the course of the disease.
5. JAK2 mutational assessment. A mutation in the Janus kinase-2 (JAK2) gene (V617F) has been identified in approximately 50% of patients with PMF and may play a role in the propagation of the disease. Moreover, mutations in calreticulin (CALR) or the thrombopoietin receptor (MPL) may be seen. However, the presence or absence of a mutation does not rule in or rule out the diagnosis.
ii. Treatment. The goal of therapy is to minimize symptoms related to the PMF. Prognostic scoring systems are often used to determine the appropriate treatment pathway.
1. Supportive measures include blood and platelet transfusions as needed. Androgens can occasionally increase RBC counts and may be used in select cases. Thalidomide or lenalidomide may be given in an attempt to decrease transfusion requirements, especially of platelets.
2. Hydroxyurea can occasionally be useful in reducing spleen size or controlling thrombocytosis or leukocytosis.
3. Splenectomy or splenic irradiation may be indicated for patients with refractory pain from splenic enlargement.
4. IFN-α may help control leukocytosis and thrombocytosis when other medications fail.
5. Allogeneic bone marrow transplantation currently offers the only chance for cure, but has significant morbidity and mortality.
6. JAK inhibitors (i.e., ruxolitinib) are approved for the management of symptoms (splenomegaly, bone pain, pruritus) associated with myelofibrosis. Ruxolitinib is equally effective in patients with a JAK2 mutation as well as those without the mutation. It is not known whether JAK inhibitors modify the natural history of the disease.
iii. Prognosis. Average survival time is highly variable and ranges from 13 to 100 months. Predictive models based on a patient’s age, hemoglobin, WBC count, platelet count, and the presence of constitutional symptoms have been used to counsel patients and to guide therapeutic decision-making.
C. Myelodysplastic Syndrome. MDS is a clonal myeloid neoplasm characterized by ineffective hematopoiesis. The bone marrow is often hypercellular, and cytopenias are often noted on the peripheral smear. MDS is most often idiopathic but can be secondary to chemotherapy, chemical exposures, or radiation exposure.
a. Classification. There are currently two classification schemes: the French-American-British (FAB) classification and the WHO classification, though the latter is more commonly used today (Table 70.2).
Table 70.2 French-American-British (FAB) and World Health Organization (WHO) Classifications of Myelodysplastic Syndrome (MDS)
FAB Classification of MDS1
Refractory anemia (RA)
Anemia, <5% blasts, <15% ringed sideroblasts
MDS with single lineage dysplasia (MDS-SLD)
1 or two lines of cytopenias with 1 lineage of dysplasia; < 1% PB blasts; < 5% BM blasts
Refractory anemia with ringed sideroblasts (RARS)
Anemia, <5% blasts, ≥15% ringed sideroblasts
MDS with multilineage dysplasia (MDS-MLD)
1-3 lines of cytopenias; 2-3 lineages of dysplasia; < 1% PB blasts; < 5% BM blasts
Refractory anemia with excess blasts
Multiple cytopenias, 5–20% blasts
MDS with ring sideroblasts
1-3 lines of cytopenias and 1-3 lineages of dysplasia; >15% ring sideroblasts; <1 % PB blasts; <5% BM blasts
Refractory anemia with excess blasts in transformation2
Multiple cytopenias, 21–30% blasts
Chronic myelomonocytic leukemia (CMML)3
Variable WBC count, <20% blasts, monocyte count >1000/μL
MDS with excess blasts-1
Multiple cytopenias, 5%–9% blasts in the bone marrow
MDS with excess blasts-2
Multiple cytopenias, 10–19% blasts in the bone marrow
Multiple cytopenias with findings not classifiable in other categories
MDS with isolated del(5q)
1-3 lines of cytopenias; 1-3 lineages of dysplasia; del(5q) on cytogenetics; ,<1% PB blasts; <5% BM blasts
1 Adapted from Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51(2):189–99.
2 The WHO classification characterizes RAEB-T as acute myeloid leukemia (AML).
3 The WHO classification characterizes CMML as an MDS/MPN overlap syndrome.
4 Derived from Bennett JM. A comparative review of classification systems in myelodysplastic syndromes (MDS). Semin Oncol 2005;32:S3–10 as well as Brunning RD, et al. Myelodysplastic syndromes: introduction. In: Jaffe, ES, Harris, NL, Stein, H, Vardiman, JW, eds. World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press: Lyon 2001, p. 63.
5 Daniel A. Arber, Attilio Orazi, Robert Hasserjian, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391–2405.
b. Approach to the patient
i. Patient history. MDS is occasionally asymptomatic at diagnosis. If symptoms and signs are present, they result from one of the cytopenias. Therefore, fatigue (anemia), infection (neutropenia), and bleeding (thrombocytopenia) are common complaints.
iii. Laboratory studies. Anemia can often be seen with occasional deficits in WBC or platelet counts.
1. RBC line. Anemia is nearly universal, typically with an increased MCV, macroovalocytes, and a decreased reticulocyte count.
2. WBC line. Leukopenia is seen in 50% of patients with hypogranular neutrophils, and the pseudo–Pelger-Huet anomaly (bilobed neutrophil nuclei) is also reported.
3. Platelets. Thrombocytopenia is seen in approximately 25% of patients, and there may be hypogranular platelets.
iv. Bone marrow aspiration and biopsy are necessary to diagnose and classify MDS. The hallmark findings could include dysplasia (abnormally sharpened progenitor blood cells), increased myeloblasts (>2% but <20%), or chromosomal deletions/translocations. According to the WHO classification, when more than 20% blasts are identified, acute leukemia is diagnosed.
c. Treatment. The goal of therapy is to reduce symptoms related to cytopenias and prolong life. Mortality is often related to infections as well as the transformation into AML. Treatment decisions are often based on the patient’s prognosis, most commonly calculated by the International Prognostic Scoring System (IPSS), which includes the number of cytopenias, percentage of blasts, and specific cytogenetic changes.
i. Supportive therapy. Blood and platelet transfusions are given as needed but may eventually be complicated by alloantibody formation, which decreases cell survival.
ii. Pharmacologic therapy
1. Growth factors
a. Erythropoietin may decrease the transfusion requirement in some patients. Serum erythropoietin levels and frequency of red cell transfusion requirements can predict the likelihood of a response.
b. Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) can increase neutrophil counts and decrease the incidence of associated minor infections, but no significant survival benefit has been demonstrated. G-CSF added to erythropoietin may also increase the RBC response compared with erythropoietin alone.
2. Pyridoxine is nontoxic and improves anemia in a small number of patients with sideroblastic anemia due to metabolic changes in the vitamin B6 pathway. This should not be confused with refractory anemia with ring sideroblasts (RARS), which will not respond to vitamin B6.
3. Low-intensity chemotherapy regimens, including the hypomethylating agents—azacitidine (Vidaza) and decitabine (Dacogen)—have demonstrated activity with significantly less morbidity than intensive chemotherapy. Studies have demonstrated improved overall survival in those receiving azacitidine compared with best supportive care.
4. Intensive chemotherapy (with regimens similar to those for AML) have proved disappointing, with significant morbidity and few long-term survivors.
iii. Allogeneic bone marrow transplantation offers the only possibility of cure for the small group of eligible patients. Decisions regarding the timing of the transplantation are often made based on the IPSS score, age, and comorbidities of the patient.
d. Prognosis is based on a variety of features included in the IPSS score (which attempts to predict an overall tendency to evolve into AML). Patients with mild cytopenias and favorable cytogenetics can survive for many years. Patients with higher blast percentages and a poor risk karyotype have an increased risk for transforming to AML and significantly shorter median survival times.
Suggested Further Readings
Fenaux P, Adès L. How we treat lower-risk myelodysplastic syndromes. Blood 2013;121:4280.Find this resource:
Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood 2014;124:3529.Find this resource:
Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood 2014;123:829.Find this resource:
Spivak JL. Myeloproliferative neoplasms. N Engl J Med 2017;376:2168–81.Find this resource: